〔Abstract〕 Objective To investigate the role of Epac1/CaMK Ⅱ signaling pathway in myocardial ischemia reperfusion injury(MIRI) in mice, and to investigate the protective effect of vitexin(VT) on acute MIRI. Methods C57/BL mice were randomly divided into 5 groups: Sham surgery group(Sham),ischemia reperfusion group(I/R),and ischemia reperfusion+vitexin group(function 3,6,12 mg/kg groups).Ligation of the left anterior descending coronary artery(LAD coronary artery) in mice resulted in ischemia of part of the heart tissue for 30min and reperfusion of the blood for 120min.Mouse myocardial ischemia reperfusion injury(MIRI) model was established.In the sham operation group, only the LAD was not ligated.Serum LDH levels of mice were detected.Hematoxylin-eosin(H&E) staining was performed on the left ventricular myocardium of mice to observe the histopathological changes.The expression level of Epac1 in myocardial tissue was observed by immunohistochemistry.The protein expressions of Epac1,Rap1,CaMK Ⅱ and ERK/p-ERK were determined by Western Blot. Results Compared with Sham group, serum LDH level of mice in I/R group was significantly increased, protein expressions of Epac1,Rap1 and CaMK Ⅱ in myocardial tissue were significantly up-regulated, and ERK1/2 phosphorylation level was decreased.Compared with I/R group, vitexin(3,6,12 mg/kg) pretreatment group decreased serum LDH level, inhibited Epac1,Rap1 and CaMK Ⅱ protein expression in mouse myocardial tissue, and promoted ERK1/2 phosphorylation(P<0.05 orP<0.01).The histopathological results showed that the myocardial fibers in the I/R group were disordered and broken, with increased gaps and obvious inflammatory cell infiltration.In the vitexin treatment group, the myocardial fibers were arranged more neatly and inflammatory cells were infiltrated less. Conclusion Vitexin may regulate Epac1/CaMK Ⅱ signaling pathway, down-regulate CaMK Ⅱ protein expression, increase ERK phosphorylation, and effectively reduce MIRI.